This invention relates to a method of preparing a polymorph of terfenadine. More particularly, the invention relates to a method for reproducibly obtaining substantially pure higher melting point polymorph(s) of terfenadine. "Higher melting point terfenadine" (hereinafter referred to as "HMP terfenadine") is defined as polymorph(s) of terfenadine having a melting point in crystalline form of from about 148.5.degree. C. to about 151.degree. C.
Terfenadine is a histamine H.sub.1 -receptor antagonist with the chemical name alpha-(p-tert-butylphenyl)-4-(hydroxy-diphenylmethyl)-1-piperidinebutanol, or alpha-(p-tert-butylphenyl)-4-(alpha-hdroxy-alpha-phenlybenzyl)-1-piperidin ebutanol. Terfenadine is a non-sedating antihistamine and is the active ingredient in Merrell Dow pharmaceuticals Inc.'s Seldane.RTM. brand pharmaceutical dosage form.
Prior methods of crystallizing terfenadine have produced a product which, while apparently chemically pure, nonetheless exhibits a widely variable melting point. For example, U.S. Pat. No. 3,878,217 discloses alpha-aryl-4-substituted piperidinoalkanol derivatives and methods for their preparation. Terfenadine is an alpha-aryl-4-substituted piperidinoalkanol derivative. Example I of the '217 patent discloses a method for preparing what appears to be a polymorphic mixture of terfenadine (or "mixed polymorph terfenadine") having a melting point of 146.5.degree. C. to 148.5.degree. C. The method disclosed utilizes terfenadone hydrochloride as the starting material and includes the step of adding methanolic potassium hydroxide to render the terfenadone hydrochloride solution basic.
U.S. Pat. No. 4,742,175 discloses methods for the preparation of polymorphic forms of terfenadine having melting points of 149.degree.-151.degree. C. and of about 146.degree.. Crystalline terfenadine having a melting point of 149.degree.-151.degree. C. is prepared using a "lower alkanol solvent".
It is well known that the particular solvent effective in the crystallization of a product is both of fundamental importance to the particular crystallization desired and of low predictability, determinable only by experimentation. See, for example, F.G. Mann et al, Practical Organic Chemistry, pp. 13-18, 4th Ed. 1960, and B.S, Furniss et al, Vogel's Textbook of Practical Organic Chemistry, pp. 105-113, 4th Ed. 1978.
Polymorphism is the crystallization of the same compound in different crystalline forms. Polymorphic transformations do not involve a molecular change but, rather a physical change. Polymorphism is very common in the pharmaceutical industry. Drugs that crystallize in different forms exhibit a wide range of chemical and physical properties, including different melting points and spectral properties. The crystalline form of drugs is particularly important since the dissolution rates, bioavailability, chemical reactivity and physical stability of a even a chemically pure solid state drug can vary with the particular crystalline form of the drug. Haleblian, J. and McCrone, W.C. (1969), J.Pharm.Sci., 58, 911; Byrn, S. (1976), J.Pharm.Sci., 65, 1. Methods for the reproducible production of substantially polymorphically pure drugs are therefore very much in demand.
Applicants have discovered methods for the reproducible preparation of substantially pure HMP terfenadine on both laboratory and commercial production scales. These methods permit the use of free-base terfenadone as the starting material and therefore do not require the addition of caustic hydroxides such as methanolic potassium hydroxide to neutralize solutions of terfenadone hydrochloride. Moreover, unlike prior art methods, applicants'methods utilize a ketone or ester solvent in the crystallization of the final product from crude terfenadine.